Mental retardation is the most common cause of handicap in children and young adults and accounts for 2-3% in the general population. X-linked mental retardation (XLMR) occurs in 1 in 600 males and is genetically heterogeneous. Among the estimated more than 150-200 responsible loci on the X chromosome, less than 40 genes have been cloned. Delineation of the molecular basis of XLMR will contribute to our understanding of human cognitive development, and will lead to development of strategies for clinical management of XLMR patients. The candidate is interested in the study of the molecular mechanism of XLMR, with a long-term career goal to become a successful clinician scientist. To accomplish this goal, he developed a comprehensive career development plan to be carried at the Johns Hopkins University. There are three key components to the research plan: (1) training in bioinformatics and genomic research; (2) training in the clinical evaluation and care for patients with mental retardation; and (3) training in the patient-oriented clinical investigation. The candidate will attend graduate courses and seminars on genome research and on principles of clinical investigation. He will receive mentored training in clinical evaluation and care for patients with mental retardation. He will be responsible for the development of a clinical research protocol for this project. In addition, the candidate will participate in the weekly Genetic Clinic at the Johns Hopkins Hospital and the Mental Retardation Clinic at the Kennedy Krieger Institute. He has developed a strategy of using human X chromosome-specific cDNA microarray to identify responsible genes. This approach is designed to detect mutations that result in a change in the abundance of mRNA due to mechanism such as promoter mutations, gene deletions, and nonsense or frameshift mutations associated with nonsense-mediated mRNA decay. Once a candidate gene is identified, Northern blot and real-time PCR will be used to verify mRNA reduction followed by mutation analysis in the proband. Additional in vitro and in vivo studies will then be carried out to delineate the molecular mechanism of XLMR for each identified gene. Through the combined laboratory research and clinical training, the candidate wishes to develop a solid knowledge base and gain precious experiences in research and clinical care for patients with mental retardation. This will be invaluable to the advancement of the candidate's career to become an independent physician scientist.